3TZM

TGF-beta Receptor type 1 in complex with SB431542

Summary for 3TZM

• Entry DOI: 10.2210/pdb3tzm/pdb
• Descriptor: TGF-beta receptor type-1, 4-[5-(1,3-benzodioxol-5-yl)-4-(pyridin-2-yl)-1H-imidazol-2-yl]benzamide (3 entities in total)
• Functional Keywords: alk5, sb431542, kinase domain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein: P36897
• Total number of polymer chains: 1
• Total formula weight: 35612.94

Authors

Ogunjimi, A.A.,Zeqiraj, E.,Ceccarelli, D.F.,Sicheri, F. (deposition date: 2011-09-27, release date: 2012-05-23, Last modification date: 2023-09-13)

Primary citation

Ogunjimi, A.A.,Zeqiraj, E.,Ceccarelli, D.F.,Sicheri, F.,Wrana, J.L.,David, L.
Structural Basis for Specificity of TGFbeta Family Receptor Small Molecule Inhibitors
Cell Signal, 24:476-483, 2012

PubMed Abstract: Transforming growth factor-β (TGFβ) receptor kinase inhibitors have a great therapeutic potential. SB431542 is one of the mainly used kinase inhibitors of the TGFβ/Activin pathway receptors, but needs improvement of its EC(50) (EC(50)=1 μM) to be translated to clinical use. A key feature of SB431542 is that it specifically targets receptors from the TGFβ/Activin pathway but not the closely related receptors from the bone morphogenic proteins (BMP) pathway. To understand the mechanisms of this selectivity, we solved the crystal structure of the TGFβ type I receptor (TβRI) kinase domain in complex with SB431542. We mutated TβRI residues coordinating SB431542 to their counterparts in activin-receptor like kinase 2 (ALK2), a BMP receptor kinase, and tested the kinase activity of mutated TβRI. We discovered that a Ser280Thr mutation yielded a TβRI variant that was resistant to SB431542 inhibition. Furthermore, the corresponding Thr283Ser mutation in ALK2 yielded a BMP receptor sensitive to SB431542. This demonstrated that Ser280 is the key determinant of selectivity for SB431542. This work provides a framework for optimising the SB431542 scaffold to more potent and selective inhibitors of the TGFβ/Activin pathway.

PubMed: 21983015
DOI: 10.1016/j.cellsig.2011.09.027

Experimental method

X-RAY DIFFRACTION (1.7 Å)